Glycogen storage disease due to muscle glycogen phosphorylase deficiency
General Information (adopted from Orphanet):
Synonyms, Signs:
PYGM DEFICIENCY
MUSCLE GLYCOGEN PHOSPHORYLASE DEFICIENCY
GSD V
GSD5
GSD due to muscle glycogen phosphorylase deficiency
GSD type 5
Glycogenosis due to muscle glycogen phosphorylase deficiency
Glycogen storage disease type 5
mcardle disease
myophosphorylase deficiency
Glycogenosis type 5
McArdle disease is an autosomal recessive metabolic disorder characterized by onset of exercise intolerance and muscle cramps in childhood or adolescence. Transient myoglobinuria may occur after exercise, due to rhabdomyolysis. Severe myoglobinuria may lead to acute renal failure. Patients ...McArdle disease is an autosomal recessive metabolic disorder characterized by onset of exercise intolerance and muscle cramps in childhood or adolescence. Transient myoglobinuria may occur after exercise, due to rhabdomyolysis. Severe myoglobinuria may lead to acute renal failure. Patients may report muscle weakness, myalgia, and lack of endurance since childhood or adolescence. Later in adult life, there is persistent and progressive muscle weakness and atrophy with fatty replacement. McArdle disease is a relatively benign disorder, except for possible renal failure as a complication of myoglobinuria (summary by Chen, 2001)
Dawson et al. (1968) suggested a test for detection of asymptomatic heterozygotes based on the development of brief painful cramps during exercise.
Ross et al. (1981) used (31)P nuclear magnetic resonance to study McArdle disease. The inorganic ...Dawson et al. (1968) suggested a test for detection of asymptomatic heterozygotes based on the development of brief painful cramps during exercise. Ross et al. (1981) used (31)P nuclear magnetic resonance to study McArdle disease. The inorganic phosphate resonance gives a direct measurement of intracellular cytoplasmic pH in muscle. During exercise, the pH fell relatively little, while phosphocreatine was shown to fall during aerobic exercise and was rapidly exhausted during minimal ischemic exercise. The ischemic forearm exercise test for McArdle disease invariably causes muscle cramps and pain in patients with this glycolytic defect. Kazemi-Esfarjani et al. (2002) investigated an alternative diagnostic exercise test in 9 patients with McArdle disease, 1 patient with the partial glycolytic defect phosphoglycerate mutase deficiency (261670), and 9 matched, healthy subjects. The classic ischemic forearm protocol was compared with the identical protocol without ischemia. All patients developed pain and cramps during the ischemic test (4 had to abort the test prematurely), whereas none experienced cramps in the nonischemic test, which all completed. Blood was sampled in the median cubital vein of the exercised arm. Plasma lactate levels increased similarly in healthy subjects during ischemic and nonischemic tests and decreased similarly in McArdle patients. Post-exercise peak lactate-to-ammonia ratios clearly separated patients and healthy controls. Similar differences in lactate-to-ammonia ratios between patients and healthy subjects were observed in 2 other work protocols using intermittent handgrip contraction at 50%, and static handgrip exercise at 30%, of maximal voluntary contraction force
The original patient of McArdle (1951) was a 30-year-old man who experienced first muscle pain and then weakness and stiffness with exercise of any muscle, including the masseters. Symptoms disappeared promptly with rest. Blood lactate did not increase after ...The original patient of McArdle (1951) was a 30-year-old man who experienced first muscle pain and then weakness and stiffness with exercise of any muscle, including the masseters. Symptoms disappeared promptly with rest. Blood lactate did not increase after exercise, suggesting that the patient was unable to convert muscle glycogen into lactate. Schmid and Mahler (1959) and Mommaerts et al. (1959) identified the cause of the disorder as a glycogenolytic defect in the muscle with the absence of muscle phosphorylase. Engel et al. (1963) observed onset of first manifestations at age 49 in a sister and brother. The sister had progressive generalized muscular weakness without cramps and had complete absence of enzyme. The brother had muscle cramps after exercise and about 35% normal activity of phosphorylase. Neither had myoglobinuria. Grunfeld et al. (1972) found evidence for the existence of 2 forms of McArdle disease, i.e., CRM-positive and CRM-negative forms. They also observed renal failure from acute rhabdomyolysis in 2 patients. They noted that the muscle cramps are 'electrically silent,' showing no activity on electromyography, which may lead to interpretation of psychoneurosis. Braakhekke et al. (1986) studied the 'second wind' phenomenon which was first described in this disorder by Pearson et al. (1961). During the first 15 minutes the 3 patients they studied experienced progressive fatigue and weakness of exercised muscles, with rapid and complete recovery (adaptation phase). Following this, all 3 patients were able to continue exercise without difficulty ('second wind' phase). The processes occurring during the 'second wind' phase included an increase in cardiac output, changes in the metabolic pathways, and an increase in EMG activity, which probably represented recruitment of more motor units to compensate for a failure of force generation in the muscle fibers. Chui and Munsat (1976) described a 40-year-old woman with myophosphorylase deficiency and the clinical features of McArdle syndrome, including exercise intolerance, muscle cramping, and myoglobinuria. The family history was unusual in that 4 other family members were also affected: an older sister, a younger brother, a 10-year-old son, her 75-year-old mother, and possibly her maternal grandmother. The authors postulated dominant inheritance. Schmidt et al. (1987) described the disorder in 2 generations, but in their family, as in the family of Chui and Munsat (1976), the enzyme defect was not proven biochemically in all persons. In the family reported by Schmidt et al. (1987), a 17-year-old boy and his 38-year-old mother were both clinically affected. Muscle phosphorylase activity in the son was 0.6% of normal. The mother had 20% activity level and the father 45%; the mother may have been a manifesting heterozygote. Papadimitriou et al. (1990) reported 2 patients with McArdle disease from the same pedigree. The first patient had progressive muscle weakness and atrophy with a residual phosphorylase enzyme activity of 28%. The second patient had typical McArdle disease, clinically and biochemically. The authors concluded that the first patient was a heterozygote and the second was a homozygote, the genetic transmission being autosomal recessive. Wu et al. (2011) reported 6 unrelated patients with McArdle disease. All had typical features of the disorder, including exercise intolerance, decreased or absent PYGM activity and immunostaining in muscle samples, and increased serum creatine kinase. All had the 'second wind' phenomenon. Three had rhabdomyolysis and myoglobinuria. Muscle biopsy of 5 patients showed glycogen accumulation. Three patients who underwent the nonischemic forearm exercise test showed flat cubital venous plasma lactate levels after exercise. Although the median age at diagnosis was 29.5 years, most recalled having onset of symptoms in childhood or adolescence. - Clinical Variability DiMauro and Hartlage (1978) described an infant with severe McArdle disease. She developed generalized, rapidly progressive weakness at age 4 weeks and died at age 13 weeks of respiratory failure. Muscle showed complete lack of phosphorylase activity, and absence of the enzyme protein was suggested by immunodiffusion studies. Milstein et al. (1989) reported a premature infant with McArdle disease who showed joint contractures and signs and symptoms of perinatal asphyxia. The parents were consanguineous. The authors noted the wide clinical spectrum of the disorder. Kost and Verity (1980) reported an affected patient in whom immobilizing cramps, stiffness, and muscle swelling began abruptly at age 60, after a life of physical vigor. Abarbanel et al. (1987) described a 59-year-old man with myophosphorylase deficiency who presented with long-standing painless and relatively static weakness starting in early childhood. EMG was myopathic, serum CK was elevated, and muscle biopsy showed accumulations of glycogen. Biochemical studies showed absence of myophosphorylase activity. Abarbanel et al. (1987) noted the unusual course and emphasized the clinical heterogeneity of the disorder
Vissing et al. (2009) reported 2 unrelated patients, ages 30 and 39 years, respectively, with a mild form of McArdle disease caused by compound heterozygosity for PYGM mutation. Each patient carried 1 typical mutation (R50X; 608455.0001 and G205S; 608455.0002) ...Vissing et al. (2009) reported 2 unrelated patients, ages 30 and 39 years, respectively, with a mild form of McArdle disease caused by compound heterozygosity for PYGM mutation. Each patient carried 1 typical mutation (R50X; 608455.0001 and G205S; 608455.0002) and 1 splice site mutation (608455.0018 and 608455.0019). The splice site mutations were found to cause aberrant splicing and production of abnormally spliced proteins that were expressed in small amounts. Biochemical studies showed 1.0 to 2.5% residual PYGM activity, suggesting that the mutations were 'leaky' and allowed some normally spliced products to be generated. Both patients reported muscle cramps, pain, and episodes of rhabdomyolysis and myoglobinuria after exercise. One had 2 to 3 episodes, whereas the other had more than 10 with 1 episode of renal failure. Both also had increased serum creatine kinase, similar to patients with typical disease. However, both patients also had a high capacity for sustained exercise. Exercise testing showed an intermediate phenotype between controls and individuals with typical McArdle disease. The patients could complete 60 minutes of ischemic exercise before muscle cramping occurred, and peak oxidative capacity was about 2-fold higher compared to patients with typical McArdle disease. The findings indicated that very low levels of PYGM are sufficient to sustain glycogenolysis and muscle oxidative metabolism, and provided the first genotype/phenotype correlation at the molecular level
Among 40 patients with McArdle disease, Tsujino et al. (1993) identified 3 point mutations in the PYGM gene (608455.0001-608455.0003). Thirty-three patients were adults with typical clinical manifestations of the disease, 6 were children, including 3 sibs, and 1 was ...Among 40 patients with McArdle disease, Tsujino et al. (1993) identified 3 point mutations in the PYGM gene (608455.0001-608455.0003). Thirty-three patients were adults with typical clinical manifestations of the disease, 6 were children, including 3 sibs, and 1 was an infant reported by DiMauro and Hartlage (1978) who died of the disease at 13 weeks. Eighteen patients, including the infant, were homozygous for the same nonsense mutation, arg50-to-ter (R50X; 608455.0001), originally reported as R49X. Twelve other patients had an R50X allele in compound heterozygosity with another mutation in the PYGM gene; the R50X mutation was thus present in 75% of patients. In 1 family with apparent autosomal dominant inheritance, the mother was a compound heterozygote and the asymptomatic father carried 1 different mutation. Martin et al. (2001) performed mutation analysis on DNA from 54 Spanish patients (40 families) with glycogen storage disease V and found that 78% of the mutant alleles could be identified with RFLP analysis for R50X, G205S (608455.0002) originally reported as G204S, and W797R (608455.0015). They also identified 6 novel mutations in the PYGM gene. Martin et al. (2001) found no clear genotype-phenotype correlations. Garcia-Consuegra et al. (2009) used skeletal muscle mRNA and cDNA analysis to identify a second defect in the PYGM gene in 4 patients with McArdle disease in whom heterozygous PYGM mutations were initially detected by genomic DNA analysis. They identified a large deletion and splice site mutation in 1 patient each and a synonymous (K215K) substitution in exon 5 in 2 patients. Real-time PCR of muscle from 1 patient with the K215K substitution showed a drastic decrease in mRNA, implicating nonsense-mediated mRNA decay as a mechanism. In 5 unrelated patients with McArdle disease, Wu et al. (2011) identified compound heterozygosity for the common R50X mutation and another pathogenic mutation in the PYGM gene (see, e.g., D51G, 608455.0020). A sixth patient was homozygous for a small deletion (608455.0021). - Genetic Modifiers In 47 patients with myophosphorylase deficiency, Martinuzzi et al. (2003) found an association between increased clinical severity and the D allele of the ACE insertion/deletion (I/D) polymorphism (106180.0001). The authors noted that the ACE I/D polymorphism is associated with muscle function and thus may modulate some clinical aspects of myophosphorylase deficiency, which may account for some of the phenotypic variability of the disorder
Glycogen storage disease type V (GSDV) is suspected in individuals with the following:...
DiagnosisClinical DiagnosisGlycogen storage disease type V (GSDV) is suspected in individuals with the following:Exercise-induced muscle cramps and painEpisodes of myoglobinuriaSupportive laboratory findings (i.e., an increased resting serum creatine kinase [CK] concentration and no change in plasma lactate concentration on the forearm non-ischemic or ischemic test) The diagnosis is confirmed either by assay of myophosphorylase enzyme activity or by molecular genetic testing.TestingSerum creatine kinase (CK) activity. A wide range of persistently elevated activities is seen, with values usually approximately 1,000 IU/L (normal reference values: <170 IU/L).Lactate forearm tests The non-ischemic lactate forearm test, the preferred lactate forearm test, relies on sampling plasma lactate concentration and plasma ammonia concentration at baseline and within the first two minutes following exercise consisting of repeated maximal one-second handgrips every other second for one minute (30 contractions). Diagnostic changes in plasma lactate concentration and plasma ammonia concentration always occur within the first two minutes after exercise [Kazemi-Esfarjani et al 2002]. Note: (1) Persons with a glycogen storage disease have exaggerated responses of plasma ammonia concentration to exercise; therefore, measuring plasma ammonia concentration is as informative as measuring plasma concentration of lactate. (2) The non-ischemic lactate forearm test [Kazemi-Esfarjani et al 2002] has the same diagnostic power as the ischemic lactate forearm test but eliminates the cramps, pain, and potential muscle injury produced by the ischemic test. In controls, plasma lactate concentrations increase five to six times above basal values. In individuals with GSDVThe plasma lactate concentration does not increase (the so-called "flat lactate curve").Post-exercise lactate-to-ammonia peak ratios are clearly decreased.The ischemic lactate forearm test was used until recently to assess the response of plasma lactate concentration to exercise in individuals with GSDV. Drawbacks to the lactate forearm ischemic test include:False positive results in weak or unmotivated personsLack of specificity for GSDV (i.e., the test is positive with any block in glycogenolysis or glycolysis)Pain and risk of local muscle damage resulting in myoglobinuria or compartment syndromeCycle test. This physiologic test in which only heart rate needs to be monitored takes advantage of the pathognomonic heart rate response of the second wind phenomenon manifest by all individuals with GSDV. A controlled case study [Vissing & Haller 2003a] indicates that cycling at a moderate, constant workload provides a specific, sensitive, and simple diagnostic test for GSDV.Myophosphorylase enzyme activity. Myophosphorylase E.C. 2.4.1.1 is the muscle isoenzyme of glycogen phosphorylase. Qualitative histochemistry or quantitative biochemical analysis in a muscle biopsy or muscle homogenate is diagnostic. The residual activity of myophosphorylase in GSDV is virtually undetectable. Molecular Genetic Testing Gene. PYGM, encoding myophosphorylase (glycogen phosphorylase, muscle form), is the only gene known to be associated with GSDV.Clinical testingTargeted mutation analysisp.Arg50*, a nonsense mutation at codon 50 in exon 1, is the most common mutation causing GSDV among individuals of European and US descent [Andreu et al 1998, Martín et al 2001, Bruno et al 2006, Aquaron et al 2007, Deschauer et al 2007, Rubio et al 2007a]. p.Arg50* has never been found in individuals of Japanese descent.p.Gly205Ser is the second most common mutation, accounting for approximately 9% of mutant alleles in various European and US populations.Sequence analysis of the entire coding region of PYGM [Kubisch et al 1998]Ethnic background must be taken into account when molecular genetic testing is performed because of the presence of relatively common mutations in specific populations (Table 1).Table 1. PYGM Mutations Other than p.Arg50* and p.Gly205Ser with Relatively High Frequency in Specific PopulationsView in own windowPopulationMutationFrequency Japanese 1p.Phe710del 64%Spanish 2p.Trp798Arg 17%Central European 3p.Tyr85* 25%1. Tsujino et al [1994]2. Fernández et al [2000], Rubio et al [2000], Martín et al [2001], Rubio et al [2007a]3. Deschauer et al [2003], Martín et al [2004]Table 2. Summary of Molecular Genetic Testing Used in Glycogen Storage Disease Type VView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPYGMTargeted mutation analysis 2p.Arg50* 32%-85%Clinicalp.Gly205Ser9%-10%Sequence analysisSequence variants 397%-100%1. The ability of the test method used to detect a mutation that is present in the indicated gene. Percentages taken from Bartram et al [1993], Tsujino et al [1993], el-Schahawi et al [1996], Andreu et al [1998], Martín et al [2001], Bruno et al [2006], Aquaron et al [2007], Deschauer et al [2007], Rubio et al [2007a]. 2. p.Lys543Thr is included in some panels but is not commonly seen in individuals with GSDV.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm the diagnosis in a probandClinical description of the type of exercise that precipitates the symptoms and a lactate forearm non-ischemic testIf clinical findings and a lactate forearm test suggest a defect in muscle glycolysis or in glycogen metabolism, molecular genetic testing is recommended: For the more common PYGM mutations (p.Arg50* and p.Gly205Ser); If no mutation or only one mutation is identified, sequence analysis of the entire coding region can be considered; In some specific populations (e.g., Spaniards) a molecular diagnostic flowchart has been proposed: sequential testing for the three common mutations in this population followed by sequence analysis of several PYGM hot-spot exons (i.e., 1, 14, 17, and 18) [Martín et al 2001, Rubio et al 2007a].If molecular genetic testing is not available or does not show homozygosity or compound heterozygosity for the common PYGM alleles, myophosphorylase enzyme activity should be analyzed histochemically and/or measured biochemically in muscle homogenates.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersAn extremely rare infantile myopathy has been associated with the common PYGM mutation p.Arg50* [el-Schahawi et al 1997].
Glycogen storage disease type V is a metabolic myopathy with onset typically in the second to third decade of life. Clinical heterogeneity exists; some individuals have mild symptoms manifesting as fatigue or poor stamina without cramps, whereas a severe, rapidly progressive form manifests shortly after birth. In some individuals, progressive weakness manifests in the sixth or seventh decade of life [Wolfe et al 2000]. The fixed weakness that occurs in approximately one third of affected individuals is more likely to involve proximal muscles and is more common in individuals over age 50 years. Most individuals learn to adjust their daily activities and can lead relatively normal lives....
Natural HistoryGlycogen storage disease type V is a metabolic myopathy with onset typically in the second to third decade of life. Clinical heterogeneity exists; some individuals have mild symptoms manifesting as fatigue or poor stamina without cramps, whereas a severe, rapidly progressive form manifests shortly after birth. In some individuals, progressive weakness manifests in the sixth or seventh decade of life [Wolfe et al 2000]. The fixed weakness that occurs in approximately one third of affected individuals is more likely to involve proximal muscles and is more common in individuals over age 50 years. Most individuals learn to adjust their daily activities and can lead relatively normal lives.The usual presentation of GSDV is exercise intolerance, including stiffness or weakness of the muscles being used, myalgia, and fatigue in the first few minutes of exercise. These symptoms are usually precipitated by isometric exercise (e.g., weight lifting) and sustained aerobic exercise (e.g., stair-climbing and jogging), and typically are relieved by rest. Any skeletal muscle can be affected. Many individuals remember painful symptoms from early childhood, but the disorder is rarely diagnosed before adulthood. Some people notice a worsening of their symptoms in middle age that may be accompanied by some muscle wasting. Presentation with exertional dyspnea has been described [Voduc et al 2004].Most individuals learn to improve their exercise tolerance by exploiting the "second wind" phenomenon, a unique feature of GSDV, that is, relief of myalgia and rapid fatigue after a few minutes of rest. The metabolic events underlying the second wind are the increased supply of glucose and free fatty acids produced from extramuscular sources as exercise progresses, leading to a switch in metabolic pathways from endogenous glycolysis to oxidative phosphorylation of blood-borne fatty acids [Haller & Vissing 2002]. The ability to develop a second wind is greatly increased in those who keep physically fit through aerobic exercise, such as walking. In contrast, sustained or strenuous exercise, such as weight lifting or sprinting, carries a high risk of muscle damage. Continuing to exercise in the presence of severe pain also results in muscle damage (rhabdomyolysis) and myoglobinuria, with the attending risk of acute renal failure.Myoglobinuria occurs in approximately 50% of individuals following intense exercise; approximately 50% of these individuals develop acute renal failure. Kidney failure is almost always reversible, but emergency treatment is required.Other presentations of GSDV:Acute renal failure in the absence of exertion [Walker et al 2003, Sidhu & Thompson 2005]Hyper-CK-emia (asymptomatic elevations of serum creatine kinase) up to 17,000 IU/L in the infantile myopathy [Ito et al 2003]. Hyper-CK-emia has been reported in adolescents [Gospe et al 1998, Bruno et al 2000].Clumsiness, lethargy, and slow movement observed in eight pre-adolescents [Roubertie et al 1998]Pathophysiology. The two types of exercise:Aerobic exercise includes walking, gentle swimming, jogging, and cycling. During aerobic exercise, the fuel used by skeletal muscle depends on several factors, including: type, intensity, and duration of exercise; physical condition; and dietary regimen. Because aerobic exercise favors the utilization of blood-borne substrates, such as fatty acids, it is better tolerated by individuals with GSDV and thus beneficial as a therapeutic regimen.Anaerobic exercise is intense but cannot be sustained (e.g., weight lifting or 100-meter dash). Normally, during anaerobic exercise, myophosphorylase converts glycogen to glucose, which enters the glycolytic pathway and produces ATP anaerobically.The first few minutes of any exercise are usually anaerobic. Depending on intensity and duration of the exercise, muscle uses different fuel sources such as anaerobic glycolysis, blood glucose, muscle glycogen, and aerobic glycolysis, followed by fatty acid oxidation.At rest the main energy source is blood free fatty acids. These molecules are oxidized in the mitochondrial beta-oxidation pathway to produce acetyl-CoA, which is further metabolized through the Krebs cycle and the mitochondrial respiratory chain resulting in ATP production.
Several studies in European populations did not observe any apparent correlation between severity of clinical findings and genotype [Martín et al 2001, Bruno et al 2006, Aquaron et al 2007, Deschauer et al 2007]....
Genotype-Phenotype CorrelationsSeveral studies in European populations did not observe any apparent correlation between severity of clinical findings and genotype [Martín et al 2001, Bruno et al 2006, Aquaron et al 2007, Deschauer et al 2007].One study showed that an angiotensin converter enzyme (ACE) insertion/deletion (I/D) polymorphism, involving the insertion (allele I) or deletion (allele D) situated approximately 250 bp into intron 16 of ACE, could play a significant role as a phenotype modulator in individuals with GSDV [Martinuzzi et al 2003]. The ACE I allele has been associated with a higher functional capacity in affected females [Gómez-Gallego et al 2008]. In the study of 99 individuals with McArdle syndrome that assessed the possible effect of several genotype modulators (ACE-I/D, AMPD1: p.Gln12*; PPARGC1A: p.Gly482Ser; ACTN3: p.Arg577*) on clinical severity, no significant relationships were detected except for the ACE D allele and the disease severity score described by Martinuzzi et al [2003] and Rubio et al [2007b].
The differential diagnosis of glycogen storage disease type V (GSDV) includes the following:...
Differential DiagnosisThe differential diagnosis of glycogen storage disease type V (GSDV) includes the following:Mitochondrial myopathy (See Mitochondrial Disorders Overview.)Myodenylate deaminaseCarnitine palmitoyl transferase II deficiencyPhosphoglycerate kinase deficiencyPhosphoglycerate mutase deficiencyPhosphofructokinase deficiencyLactate dehydrogenase deficiencyPhosphorylase b kinase deficiencyIdiopathic hyper-CK-emiaVery long-chain acyl-CoA dehydrogenase (VLCAD) deficiencyMitochondrial trifunctional protein (MTP) deficiencyNote to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).GSDV – infantile onset: GSDV – adult onset:
To establish the extent of disease in an individual diagnosed with glycogen storage disease type V (GSDV), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with glycogen storage disease type V (GSDV), the following evaluations are recommended:Physical examination with emphasis on muscle strength/weaknessSerum CK concentrationTreatment of ManifestationsAerobic training (on a regular diet). In some individuals, improvement in exercise and circulatory capacity has been reported, probably caused by the increased circulatory capacity, which facilitates delivery of blood-borne fuels [Haller 2000]. In eight individuals who underwent a 14-week aerobic conditioning program in which they pedaled a cycloergometer for 30-40 minutes a day, four days a week at an intensity corresponding to 60% to 70% of maximal heart rate, an increase in work capacity, oxygen uptake, cardiac output, citrate synthase activity, and beta-hydroxyacyl coenzyme A dehydrogenase activity were observed, indicating that moderate aerobic exercise improves exercise capacity in individuals with McArdle disease [Haller et al 2006]. Nine individuals who underwent an eight-month supervised aerobic exercise training program including five weekly sessions of walking and/or cycling for no more than 60 minutes, improved their peak power output, peak oxygen uptake, and ventilatory threshold with no evidence of negative outcomes, suggesting that under carefully controlled conditions individuals with McArdle disease may exercise safely and may respond favorably to training [Maté-Muñoz et al 2007].Creatine monohydrate in a placebo-controlled crossover trial with nine affected individuals improved symptoms and increased their capacity for ischemic, isometric forearm exercise [Vorgerd et al 2000]. This positive effect did not result from increased levels of phosphocreatine in muscle. Rather, creatine may have a quenching effect on the potassium-mediated changes in membrane excitability. A subsequent clinical trial with high doses of creatine monohydrate in 19 individuals lowered exercise intolerance [Vorgerd et al 2002]. The indication for symptomatic therapy with creatine monohydrate needs to be strengthened. Ingestion of sucrose before exercise. In a single-blind, randomized, placebo-controlled crossover study in 12 individuals with GSDV, ingestion of sucrose markedly improved exercise tolerance [Vissing & Haller 2003b]. The treatment takes effect during the time when muscle injury commonly develops in GSDV. In addition to increasing exercise capacity and sense of well-being, the treatment may protect against exercise-induced rhabdomyolysis. Ingestion of sucrose before exercise combined with an aerobic conditioning program is reasonable [Amato 2003].Three daily habits recommended by Haller [2000] to improve the quality of life:Avoid intense isometric exercise and maximal aerobic exercise, which triggers cramps and, potentially, myoglobinuria.Avoid a totally sedentary life, which induces deconditioning.Engage in regular, moderate aerobic exercise, which improves circulatory capacity and increases delivery of blood-borne fuels, a sort of permanent "second wind" (i.e., a decrease in heart rate and perceived exertion during exercise) effect [Ollivier et al 2005].Ramipril, an ACE inhibitor, used in a randomized, placebo-controlled, double-blind pilot trial in eight persons with McArdle disease, decreased disability and improved exercise physiology only in those individuals with the ACE genotype D/D [Martinuzzi et al 2008].Two systematic reviews of pharmacologic and nutritional treatments for GSDV were published in the Cochrane Database [Quinlivan & Beynon 2004, Quinlivan et al 2008]. The authors' conclusions:There is no evidence of significant benefit from any specific nutritional or pharmacologic treatment for GSDV.Low-dose creatine supplementation demonstrated a statistically significant benefit, albeit modest, in ischemic exercise in a small number of individuals.Ingestion of oral sucrose immediately prior to exercise reduces perceived ratings of exertion and heart rate and improves exercise tolerance. This treatment does not influence sustained or unexpected exercise and may cause significant weight gain.A carbohydrate-rich diet was of benefit. Because of the rarity of GSDV, multicenter collaboration and standardized assessment protocols are needed for future treatment trials.SurveillanceAppropriate surveillance includes:Annual routine physical examinationAnnual review of dietAgents/Circumstances to AvoidGeneral anesthetics. Risk of acute muscle damage is reported with certain general anesthetics (usually muscle relaxants and inhaled anesthetics), although in practice, problems appear to be rare. One report showed hyperthermia, pulmonary edema, and rhabdomyolysis [Lobato et al 1999]; however, GSDV does not seem to cause severe perioperative problems in routine anesthetic care. Nonetheless, measures for preventing muscle ischemia and rhabdomyolysis should be taken in individuals with GSDV [Bollig et al 2005]. Lipid-lowering drugs. A study in which 136 individuals with myopathy induced by one of the three lipid-lowering drugs atorvastatin, cerivastatin, and simvastatin were tested for the two more frequent PYGM mutations (p.Arg50*, p.Gly205Ser) revealed 20-fold more PYGM heterozygotes than expected for the general population [Vladutiu et al 2006]. These findings provide preliminary evidence that PYGM heterozygotes may be predisposed to statin-induced myopathy; however, because only two mutations were assessed, some individuals in this study who were presumed to be carriers could actually be compound heterozygotes. Thus, clinicians should be cautious when recommending statins to individuals who have GSDV or are PYGM mutation carriers.Evaluation of Relatives at RiskEarly diagnosis of GSDV in relatives at risk may improve long-term outcome by heightening awareness of the need to avoid repetitive episodes of muscle damage that may lead to rhabdomyolysis and fixed weakness. When the family-specific mutations are known, molecular genetic testing can be used; when the family-specific mutations are not known, a reliable and accurate diagnosis of GSDV could be reached following the criteria described in Diagnosis.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationGene therapy. An adenoviral recombinant containing the full-length human myophosphorylase cDNA was efficiently transduced into phosphorylase-deficient sheep and human myoblasts, where it restored enzyme activity [Pari et al 1999].Adenovirus and adeno-associated virus-mediated delivery of human phosphorylase cDNA and LacZ cDNA to muscle in the ovine (sheep) model of McArdle disease showed expression of functional myophosphorylase and some re-expression of the non-muscle glycogen phosphorylase isoforms (liver and brain isoforms) in regenerating fibers [Howell et al 2008].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherVitamin B6 has been used because the overall body stores of pyridoxal phosphate are depleted in GSDV. A beneficial effect has been documented in one individual, but this requires confirmation [Phoenix et al 1998]. Branched-chain amino acids (BCA). Administration of BCA as alternative fuels to glycogen to six individuals worsened bicycle exercise capacity, possibly because of the FFA-lowering effect of the amino acids [MacLean et al 1998].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Glycogen Storage Disease Type V: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPYGM11q13.1Glycogen phosphorylase, muscle formPYGM homepage - Mendelian genesPYGMData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Glycogen Storage Disease Type V (View All in OMIM) View in own window 232600GLYCOGEN STORAGE DISEASE V 608455GLYCOGEN PHOSPHORYLASE, MUSCLE; PYGMMolecular Genetic PathogenesisThe muscle glycogen phosphorylase (PYGM, glycogen phosphorylase, α-1,4-glucan orthophosphate glycosyltransferase, EC 2.4.1.1.) initiates glycogen breakdown by removing α-1,4-glucosyl residues with ATP consumption (i.e., phosphorylytically) from the outer branches of glycogen with liberation of glucose-1-phosphate. The enzyme exists as a homodimer containing two identical subunits of 97 kd each. The dimers associate into a tetramer to form the enzymatically active phosphorylase A.Normal allelic variants. PYGM spans 14 kb containing 20 exons. Five single nucleotide normal allelic variants in the coding region have been annotated, three non-synonymous and two synonymous changes have been identified (see Table 4). Ideally, synonymous exonic allelic variants found in symptomatic individuals in whom no other PYGM pathogenic mutation was identified should be tested for their potential effect on mRNA splicing [Cartegni et al 2002]. The synonymous mutation at lysine residue 609 was found to severely alter PYGM transcripts in a symptomatic individual [Fernandez-Cadenas et al 2003].Pathologic allelic variants. p.Arg50* is a so-called "common" mutation in exon 1 of PYGM that results in a premature stop codon. This mutation was identified in approximately 32%-71% of all mutant alleles [Andreu et al 1998, Martín et al 2001, Bruno et al 2006, Aquaron et al 2007, Deschauer et al 2007, Rubio et al 2007a].p.Gly205Ser is the second most frequent mutation in various European and US populations, representing approximately 9% of mutant alleles.In an analysis of 95 individuals of Spanish origin, p.Trp798Arg accounted for 12% of mutant alleles.To date, 95 mutations causing PYGM deficiency have been identified. See Table 3 for classes of mutations observed [Andreu et al 2007].Note that the synonymous mutation c.1827G>A at lysine residue 609 was found to severely alter PYGM transcripts [Fernandez-Cadenas et al 2003] (see Table 4).Table 3. Classes of Mutations Observed in PYGMView in own windowGenetic MechanismNumber of MutationsNucleotide substitutions (missense/nonsense)67Nucleotide substitutions (splicing)7Small deletions15Small insertions (including duplications)3Small indel mutations 13Total95From Bruno et al [2006], Andreu et al [2007], Aquaron et al [2007], Deschauer et al [2007], Rubio et al [2007a]1. Indel mutations (also called "indels") are the simultaneous insertion and deletion of nucleotide sequence(s) at the same site in a gene.Table 4. Selected PYGM Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change 1(Alias 2)Reference SequencesNormalc.564C>Ap.Asn188LysNM_005609.2 NP_005600.1c.1240C>Gp.Arg414Glyc.1289C>Tp.Ser430Leuc.1365C>Tp.=c.1494C>Tp.=Pathologicc.148C>Tp.Arg50* (Arg49*) c.255C>Ap.Tyr85* (Tyr84*) c.613G>Ap.Gly205Ser (Gly204Ser) c.1628A>Cp.Lys543Thr (Lys542Thr) c.1827G>Ap.= (Lys608Lys) c.2128_2130delTTCp.Phe710del (708/709del) c.2392T>Cp.Trp798Arg (Trp797Arg) See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. p.= indicates that no amino acid change is expected. 2. Variant designation that does not conform to current naming conventions. For PYGM, the alias for a pathogenic protein amino acid change was in the past one residue less, as it follows a convention of designating the second amino acid (Ser) as residue number one, rather than the standard of using the initiating Met residue as number one.Normal gene product. The size of monomeric PYGM is 841 amino acids in human skeletal muscle. PYGM protein has a molecular weight of 97 kd.Abnormal gene product. Mutations in PYGM reduce or abolish myophosphorylase enzyme activity in muscle [Dimauro et al 2002]. Missense mutations may affect contact dimer pairs, which are involved in the propagation of allosteric effects of this regulatory protein. Mutations can also disrupt hydrogen bond interactions and affect substrate or effector-/inhibitor-binding sites. Mutations yielding premature stop codons (PTC) predict truncated proteins but may also produce deep effects at the transcriptional level (i.e., nonsense mediated decay (NMD), disruption of splicing machinery yielding aberrant transcript) [Martín et al 2001, Fernandez-Cadenas et al 2003]. It should be noted that 35% of all mutations in PYGM result in PTC. One study in 28 individuals harboring 17 different mutations with PTCs showed that the NMD mechanism occurred in 92% and that the common mutation p.Arg50* elicited decay in all genotypes tested [Nogales-Gadea et al 2008].